EP2693883B1 - Monomères silyles aptes à former un multimère dans une solution aqueuse et leurs procédés d'utilisation - Google Patents

Monomères silyles aptes à former un multimère dans une solution aqueuse et leurs procédés d'utilisation Download PDF

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EP2693883B1
EP2693883B1 EP12842488.4A EP12842488A EP2693883B1 EP 2693883 B1 EP2693883 B1 EP 2693883B1 EP 12842488 A EP12842488 A EP 12842488A EP 2693883 B1 EP2693883 B1 EP 2693883B1
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alkyl
phenyl
heteroaryl
group
occurrence
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EP2693883A1 (fr
EP2693883A4 (fr
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Francis Barany
Maneesh Pingle
Donald E. Bergstrom
Sarah F. Giardina
Lee Daniel Arnold
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Cornell University
Purdue Research Foundation
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Purdue Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • protein-protein interactions For example, signaling pathways are used by cells to generate biological responses to external or internal stimuli.
  • a few thousand gene products control both ontogeny/development of higher organisms and sophisticated behavior by their many different cell types. These gene products can work in different combinations to achieve their goals and often do so through protein-protein interactions.
  • Such proteins possess modular protein domains that recognize, bind, and/or modify certain motifs. Protein-protein and protein-nucleic acid recognition often function through protein interactions domains, for example, such as the SH2, SH3, and PDZ domains. These protein-interaction domains may represent a meaningful area for developing targeted therapies.
  • Other macromolecular interactions that may serve as potential targets for effective therapies include protein-nucleic acid interactions, protein-carbohydrate interactions, and protein-lipid interactions.
  • WO 00/02896 discloses a phosphoramidite-type process for the synthesis of oligonucleotides and analogues thereof using alternative protecting groups for the phosphoramidite oxygen; and chemical intermediates used in the preparation of synthetic precursors and oligonucleotide products.
  • Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media.
  • such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo ) to form a multimer, (e.g. a dimer).
  • Contemplated monomers may include a ligand moiety (e.g. a ligand or pharmacophore for the target biomolecule), a linker element, and a connector element that joins the ligand moiety and the linker element.
  • a ligand moiety e.g. a ligand or pharmacophore for the target biomolecule
  • linker element e.g. a ligand or pharmacophore for the target biomolecule
  • a connector element that joins the ligand moiety and the linker element.
  • contemplated monomers may join together via each linker element and may thus be capable of modulating
  • a first silyl monomer capable of forming a biologically useful multimer when in contact with one, two, three or more second silyl monomers in an aqueous media is provided.
  • the first and second silyl monomer are represented by the formula: X 3 -Y 3 -Z 3 (Formula III) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein
  • a therapeutic multimer compound formed from the multimerization in an aqueous media of a first monomer X 3 -Y 3 -Z 3 with a second monomer X 3 -Y 3 -Z 3 is provided.
  • a method of treating a disease associated with a target protein or a target protein-protein interaction in a patient in need thereof comprises administering to the patient the monomer selected from X 3 -Y 3 -Z 3 (Formula IV), wherein upon administration, the silyl monomer forms a homomultimer in vivo that binds to one, two, three or more protein domains in said target protein, or to at least one protein domain in each of the proteins involved in the protein-protein interaction.
  • a first monomer capable of forming a biologically useful multimer when in contact with one, two, three or more second monomers in an aqueous media is provided.
  • the first monomer is represented by the formula: X 1 -Y 1 -Z 1 (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein
  • a method of administering a pharmaceutically effective amount of a multimeric compound to a patient in need thereof comprises administering to the patient thereof an amount of the first monomer and an amount of the second monomer in amounts effective such that the pharmaceutically effective amount of the resulting multimer is formed in vivo.
  • the invention provides, a therapeutic multimer compound formed from the multimerization in an aqueous media of the first and second monomer is provided.
  • the first monomer is represented by: X 1 -Y 1 -Z 1 (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof
  • the second monomer represented by: X 2 -Y 2 -Z 2 (Formula II) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof.
  • a method of modulating two or more target biomolecule domains substantially simultaneously comprises contacting an aqueous composition comprising said target biomolecule domains with a first monomer represented by: X 1 -Y 1 -Z 1 (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein X 1 is a first ligand moiety capable of binding to and modulating a first target biomolecule domain; and a second monomer represented by: X 2 -Y 2 -Z 2 (Formula II), wherein
  • a first monomer and a second monomer for use in treating a disease associated with two or more target biomolecule domains in a patient in need thereof comprises administering to said patient a first monomer represented by: X 1 -Y 1 -Z 1 (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein X 1 is a first ligand moiety capable of binding to and modulating a first target biomolecule domain; and administering to said patient a second monomer represented by: X 2 -Y 2 -Z 2 (Formula II), wherein X 2 is a second ligand moiety capable of binding to a second target biomolecule domain, wherein upon administration, said first monomer and said second monomer forms a multimer in vivo that binds to the first target biomolecule domain and the second target biomolecule domain.
  • a compound is selected from the group consisting of: (4-(3-(aminomethyl)phenyl)piperidin-1-yl)(4-((hydroxydimethylsilyl)methoxy)-phenyl)methanone; N-(4-(4-(3 -(aminomethyl)phenyl)-piperidine-1 -carbonyl)-2-chlorophenyl)-2-(hydroxydimethylsilyl)acetamide; N-(3-(4-(3-(aminomethyl)phenyl)piperidine-1-carbonyl)-phenyl)-2-(hydroxydimethylsilyl)acetamide; (4-(3-(aminomethyl)phenyl)piperidin-1-yl)(3-chloro-4-((hydroxydimethylsilyl)methoxy)-phenyl)methanone; (4-(3-(aminomethyl)phenyl)-piperidin-1-yl)(3-((amino
  • Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. Such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo ) to form a multimer, (e.g. a dimer).
  • Contemplated monomers may include a ligand moiety (e.g. a ligand or pharmacophore moiety), a linker element, and a connector element that joins the ligand moiety and the linker element.
  • contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.
  • contemplated monomers may be separate or separatable in a solid or in an aqueous media under one set of conditions, and when placed in an aqueous media having one or more biomolecules, with another (e.g., under a different set of conditions), can 1) form a multimer through the linker on each monomer; and either: 2a) bind to the biomolecule in two or more locations (e.g.
  • protein domains through each ligand moiety of the respective monomer or 2b) bind to two or more biomolecules through each ligand moiety of the respective monomer.
  • disclosed monomers may interact with another appropriate monomer (i.e. a monomeric pair) in an aqueous media (e.g., in vivo ) to form a multimer (e.g. a dimer) that can bind to two separate target biomolecule domains (e.g. protein domains).
  • the ligand moiety of a contemplated monomer may be a pharmacophore or a ligand moiety that is e.g., capable of binding to a biomolecule, such as for example, a protein, e.g. a specific protein domain, a component of a biological cell such as ribosome (composed of proteins and nucleic acids), or an enzyme active site (e.g. a protease, such as tryptase).
  • the linker element comprises a functional group capable of forming a chemical bond with another linker element.
  • the linker moiety may also serve as a signaling entity or "reporter," and in some instances the assembly of two or more linkers can produce a fluorescent entity or fluorophore with properties distinct from the individual linker moiety.
  • a plurality of monomers, each comprising a linker element may react to form a multimer connected by the linker elements.
  • the multimer may be formed in vivo.
  • the multimer may have enhanced properties relative to the monomers that form the multimer.
  • the multimer may bind to a target with greater affinity than any of the monomers that form the multimer. Also described are methods of making the compositions and methods of administering the compositions.
  • a plurality of monomers may assemble to form a multimer.
  • the multimer may be used for a variety of purposes. For example, in some instances, the multimer may be used to perturb a biological system. As described in more detail below, in some disclosures, the multimer may bind to a target biomolecule, such as a protein, nucleic acid, or polysaccharide. In certain disclosures, the multimer may be used as a pharmaceutical.
  • the multimer may form in vivo upon administration of suitable monomers to a subject.
  • the multimer may be capable of interacting with a relatively large target site as compared to the individual monomers that form the multimer.
  • a target may comprise, in some embodiments, two protein domains separated by a distance such that a multimer, but not a monomer, may be capable of binding to both domains essentially simultaneously.
  • contemplated multimers may bind to a target with greater affinity as compared to a monomer binding affinity alone.
  • a contemplated multimer may advantageously exhibit enhanced properties relative to the monomers that form the multimer.
  • a multimer may have improved binding properties as compared to the monomers alone.
  • a multimer may have improved signaling properties.
  • the fluorescent properties of a multimer may be different as compared to a monomer.
  • the fluorescent brightness of a multimer at a particular wavelength may be greater than the fluorescent brightness at the same wavelength of the monomers that form the multimer.
  • a difference in signaling properties between the multimer and the monomers that form the multimer may be used to detect formation of the multimer.
  • detection of the formation of the multimer may be used to screen monomers, as discussed in more detail below.
  • the multimers may be used for imaging or as diagnostic agents.
  • a multimer may be a homomultimer (i.e., a multimer formed from two or more essentially identical monomers) or may be a heteromultimer (i.e., a multimer formed from two or more substantially different monomers).
  • a contemplated multimer may comprise 2 to about 10 monomers, for example, a multimer may be a dimer, a trimer, a tetramer, or a pentamer.
  • a monomer may comprise a ligand moiety, a linker element, and a connector element that associates the ligand moiety with the linker element.
  • the linker element of a first monomer may combine with the linker element of a second monomer.
  • the linker element may comprise a functional group that can react with a functional group of another linker element to form a bond linking the monomers.
  • the linker element of a first monomer may be substantially the same as the linker element of a second monomer.
  • the linker element of a first monomer may be substantially different than the linker element of a second monomer.
  • the ligand moiety may be a pharmacophore.
  • the ligand moiety (e.g., a pharmacophore) may bind to a target molecule with a dissociation constant of less than 1 mM, in some embodiments less than 500 microM, in some embodiments less than 300 microM, in some embodiments less than 100 microM, in some embodiments less than 10 microM, in some embodiments less than 1 microM, in some embodiments less than 100 nM, in some embodiments less than 10 nM, and in some embodiments less than 1 nM.
  • the IC 50 of the first monomer against a first target biomolecule and the IC 50 of the second monomer against a second target biomolecule may be greater than the apparent IC 50 of a combination of the monomers against the first target biomolecule and the second target biomolecule (or second binding site on the first biomolecule). That is, the apparent IC 50 of a combination of the monomers against the first target biomolecule and the second target biomolecule may advantageously be lower than the IC 50 of the first monomer against a first target biomolecule and the IC 50 of the second monomer against a second target biomolecule.
  • the combination of monomers may be any suitable ratio.
  • the ratio of the first monomer to the second monomer may be between 10:1 to 1:10, in some embodiments between 5:1 and 1:5, and in some embodiments between 2:1 and 1:2. In some cases, the ratio of the first monomer to the second monomer may be essentially 1:1. In some instances, the ratio of the smaller of the IC 50 of the first monomer and the second monomer to the apparent IC 50 of the multimer may be at least 3.0. In other instances, the ratio of the smaller IC 50 of the first monomer or the second monomer to the apparent IC 50 of the multimer may be at least 10.0. In some embodiments, the ratio of the smaller IC 50 of the first monomer or the second monomer to the apparent IC 50 of the multimer may be at least 30.0.
  • the apparent IC 50 resulting from an essentially equimolar combination of monomers against the first target biomolecule and the second target biomolecule is at least about 3 to 10 fold lower, at least about 10 to 30 fold lower, at least about 30 fold lower, or at least about 40 to 50 fold lower than the lowest of the IC 50 of the second monomer against the second target biomolecule or the IC 50 of the first monomer against the first target biomolecule.
  • Affinities of heterodimerizing monomers for the target biomolecule(s) can often be assessed through the testing of the respective monomers in appropriate assays for the target activity or biology because their self-association to form homo-dimers may not be promoted by binding to the target(s).
  • the testing of homodimerizing monomers may not, in some embodiments, afford an affinity solely for the monomeric or dimeric state, but rather the observed effect (e.g. IC 50 ) is a result of the monomer-dimer dynamics and equilibrium, with the apparent binding affinity (or IC 50 ) being e.g., a weighted measure of the monomer and dimeric inhibitory effects upon the target.
  • a dimeric species may not form in detectable concentrations in solution, yet a target biomolecule may be bound primarily by the dimeric species, indicating that a dimeric species does in fact form.
  • the ability or lack of ability to detect a dimeric species in solution should not be construed as an indication of whether dimeric species is being formed.
  • the pH of the aqueous fluid in which the multimer forms may be between pH 1 and and 9, in some embodiments between pH 1 and 3, in some embodiments between pH 3 and 5, in some embodiments between pH 5 and 7, and in some embodiments between pH 7 and 9.
  • the multimer may be stable in an aqueous solution having a pH between pH 1 and 9, in some embodiments between pH 1 and 3, in some embodiments between pH 3 and 5, in some embodiments between pH 5 and 7, and in some embodiments between pH 7 and 9.
  • the aqueous solution may have a physiologically acceptable pH.
  • the ligand moiety may be capable of binding to a target and at least partially disrupting a biomolecule-biomolecule interaction (e.g., a protein-protein interaction). In some embodiments, the ligand moiety may be capable of binding to a target and at least partially disrupting a protein-nucleic acid interaction. In some cases, the ligand moiety may be capable of binding to a target and at least partially disrupting a protein-lipid interaction. In some cases, the ligand moiety may be capable of binding to a target and at least partially disrupting a protein-polysaccharide interaction. In some embodiments, the ligand moiety may be capable of at least partially stabilizing a biomolecule-biomolecule interaction. In certain embodiments, the ligand moiety may be capable of at least partially inhibiting a conformational change in a biomolecule target.
  • a biomolecule-biomolecule interaction e.g., a protein-protein interaction
  • the ligand moiety may be capable of binding to a target and at least partially disrupt
  • the linker element may be capable of generating a signal.
  • the linker element may be capable of fluorescing.
  • the linker element may have greater fluorescence when the monomer to which it is attached is part of a multimer as compared to when the monomer to which it is attached is not part of a multimer.
  • the fluorescent brightness of a linker element may increase by at least 2-fold, in some embodiments by at least 5-fold, in some embodiments by at least 10-fold, in some embodiments by at least 50-fold, in some embodiments by at least 100-fold, in some embodiments by at least 1000-fold, and in some embodiments by at least 10000-fold.
  • a linker element in a multimer may have a peak fluorescence that is red-shifted relative to the peak fluorescence of the linker element in a monomer. In other embodiments, a linker element may have a peak fluorescence that is blue-shifted relative to the peak fluorescence of a linker element in a monomer.
  • a first silyl monomer may be capable of forming a biologically useful multimer when in contact with one, two, three or more second silyl monomers.
  • the first and second silyl monomer are represented by the formula: X 3 -Y 3 -Z 3 (Formula III) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein
  • substituents R w , Q 2A , W 1 , and W 1A are oriented such that a Si-heteroatom bond does not occur (e.g., a Si-O bond, a Si-N bond, or a Si-S bond).
  • a Si-heteroatom bond e.g., a Si-O bond, a Si-N bond, or a Si-S bond.
  • R w is -O-C 1-4 alkyl-
  • the -O-C 1-4 alkyl- substituent would be oriented such that Si is bonded to the C 1-4 alkyl group (e.g., -O-C 1-4 alkyl-Si-) and not to the O atom.
  • the first silyl monomer may form a biologically useful multimer when in contact with one, two, three or more second silyl monomers in vivo.
  • the multimer may be a biologically useful dimer when the first silyl monomer is in contact with the second silyl monomer.
  • the multimer may be a biologically useful trimer when the first silyl monomer is in contact with two second silyl monomers.
  • the multimer may be a biologically useful cyclic tetramer when the first silyl monomer is in contact with three second silyl monomers.
  • the ligand moiety may be a pharmacophore and the target biomolecule may be a protein target.
  • the first target biomolecule may be a protein component of the ribosome.
  • the first target biomolecule may be a subunit of tryptase.
  • X 3 may be a non-peptidyl ligand moiety.
  • the modulating effects of the multimer formed from the silyl monomers is greater than the sum of the modulating effects of the individual monomers.
  • a first monomer may be capable of forming a biologically useful multimer when in contact with one, two, three or more second monomers in an aqueous media, wherein the first monomer is represented by the formula: X 1 -Y 1 -Z 1 (Formula I) and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein
  • Z 1 may further comprise a diol moiety.
  • the second monomer may further comprise a boronic acid or oxaborale moiety, which may be capable of binding with the Z 1 moiety.
  • Z 1 may be independently selected, for each occurrence, from the group consisting of:
  • the second monomer may be represented by: X 2 -Y 2 -Z 2 (Formula II), and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein X 2 is a second ligand moiety capable of binding to and modulating a second target biomolecule; Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2 ; Z 2 comprises one, two, three or more silyl moieties.
  • X 2 is a second ligand moiety capable of binding to and modulating a second target biomolecule
  • Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2
  • Z 2 comprises one, two, three or more silyl moieties.
  • Z 2 may further comprise a boronic acid or oxaborale moiety.
  • Z 1 and Z 2 may be independently selected, for each occurrence, from the group consisting of:
  • Z 3 , Z 2 , and Z 1 may be independently selected, for each occurrence, from Group A; wherein W 1 independently, for each occurrence, maybe absent or selected from the group consisting C 1-4 alkyl or phenyl; wherein BB may be selected independently, for each occurrence, from phenyl or heteroaryl; and wherein R 1 and R 2 may be independently selected, for each occurrence, from methyl or -OH; and wherein Q 1 may be - OH.
  • R 2 and Q 1 may be -OH.
  • Z 3 , Z 2 , and Z 1 may be independently selected, for each occurrence, from the group consisting of: wherein
  • Z 3 Z 2 , and Z 1 may be independently selected, for each occurrence, from the group consisting of: and wherein
  • Z 3 , Z 2 , and Z 1 may be independently selected, for each occurrence, from the group consisting of: wherein
  • Z 3 , Z 2 , and Z 1 may be independently selected, for each occurrence, from Group B; wherein W 1 and W 1A independently, for each occurrence, maybe absent or C 1-4 alkyl; and wherein BB may be selected independently, for each occurrence, from phenyl or heteroaryl.
  • W 1 may be -C 1-4 alkyl- and W 1A may be absent.
  • W 1 and W 1A may be -C 1-4 alkyl-.
  • W 1 and W 1A may be absent.
  • BB may be selected from the group consisting of
  • Z 3 , Z 2 , and Z 1 may be independently selected, for each occurrence, from the group consisting of: and wherein
  • Z 3 , Z 2 , and Z 1 may be independently selected, for each occurrence, from the group consisting of: and wherein
  • Z 2 may be independently selected, for each occurrence, from the group consisting of: and wherein
  • the first monomer may form a biologically useful multimer when in contact with one, two, three or more second monomers in vivo .
  • the multimer may be a biologically useful dimer when the first monomer is in contact with the second monomer.
  • the multimer may be a biologically useful trimer when the first monomer is in contact with two second monomers.
  • the multimer may be a biologically useful cyclic tetramer when the first monomer is in contact with three second monomers.
  • the ligand moiety may be a pharmacophore and the target biomolecule may be a protein target.
  • the first target biomolecule and the second target biomolecule may be the same.
  • the first target biomolecule and the second target biomolecule may be different.
  • the first target biomolecule may be a ribosome.
  • the first target biomolecule may be a tryptase.
  • the second target biomolecule may be a ribosome.
  • the second target biomolecule may be a tryptase.
  • X 1 may be a non-peptidyl ligand moiety.
  • X 2 may be a non-peptidyl ligand moiety.
  • X 1 and X 2 may be the same. In another embodiment, X 1 and X 2 may be the different.
  • the effects of the multimer formed from the monomers may be greater than the sum of the effects of the individual monomers.
  • the ratio of the smaller of the apparent IC 50 of the first monomer or the second monomer to the apparent IC 50 of the multimer may be at least 3.0, 10.0 or 30.0.
  • the first monomer and the second monomer may reversibly associate to form the multimer.
  • a monomer may be capable of reacting with one or more other monomers to form a multimer in an aqueous composition, e.g. in vivo.
  • a first monomer may react with a second monomer to form a dimer.
  • a first monomer may react with two second monomers to form a trimer.
  • a first monomer may react with three second monomers to form a cyclic tetramer.
  • each of the monomers that form a multimer may be essentially the same.
  • each of the monomers that form a multimer may be substantially different.
  • at least some of the monomers that form a multimer may be essentially the same or may be substantially different.
  • the linker element of a first monomer and the linker element of a second monomer may be substantially different.
  • the connector element of a first monomer and the connector element of a second monomer may be substantially different.
  • the ligand moiety (e.g., pharmacophore) of a first monomer and the ligand moiety (e.g. pharmacophore) of the second monomer may be substantially different.
  • formation of a multimer from a plurality of monomers may be irreversible. In some embodiments, formation of a multimer from a plurality of monomers may be reversible.
  • the multimer may have an oligomer or dimer dissociation constant between 10 mM and 1 nM, in some embodiments between 1 mM and 100 nM, in some embodiments between 1 mM and 1 ⁇ M, and in some embodiments between 500 mM and 1 ⁇ M.
  • the multimer may have a dissociation constant of less than 10 mM, in some embodiments less than 1 mM, in some embodiments less than 500 ⁇ M, in some embodiments less than 100 ⁇ M, in some embodiments less than 50 ⁇ M, in some embodiments less than 1 ⁇ M, in some embodiments less than 100 nM, and in some embodiments less than 1 nM.
  • the affinity of the multimer for the target biomolecule(s) are less than 1 ⁇ M, in some embodiments less than 1 nM, in some embodiments less than 1 pM, in some embodiments less than 1 fM, and in some embodiments less than 1 aM, and in some embodiments less than 1 zM.
  • molecular self-assembly may be directed through noncovalent interactions, e.g., hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, pi-pi interactions, electrostatic, and/or electromagnetic interactions.
  • pi-pi and pi-cation interactions can be used to drive multimerization.
  • van der Waals and electromagnetic forces are other interactions that can help to drive multimerization.
  • acid/base pairs and donor-acceptor pairs e.g., amide and/or sulfonamide pairs, can be employed to help direct self-assembly.
  • use of hydrophobic interactions can be used for multimerization targeting a membrane-bound protein.
  • metal coordination might be used when the target itself incorporates the metal, but could also be used in other scenarios.
  • a first monomer and a second monomer may form a dimer in aqueous solution.
  • the first monomer may form a biologically useful dimer with a second monomer in vivo.
  • a therapeutic multimer compound may form from the multimerization in an aqueous media of a first monomer X 3 -Y 3 -Z 3 with a second monomer X 3 -Y 3 -Z 3 .
  • a therapeutic multimer compound may form from the multimerization in an aqueous media of the first monomer represented by: X 1 -Y 1 -Z 1 (Formula I), and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, and the second monomer represented by: X 2 -Y 2 -Z 2 (Formula II), and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof.
  • X 1 is a first ligand moiety capable of binding to and modulating a first target biomolecule
  • Y 1 is absent or is a connector moiety covalently bound to X 1 and Z 1
  • Z 1 is independently selected from the groups discussed above
  • X 2 is a second ligand moiety capable of binding to and modulating a second target biomolecule
  • Y 2 is absent or is a connector moiety covalently bound to X 2 and Z 2
  • Z 2 is is independently selected from the groups discussed above.
  • X 1 and X 2 may be the same. In other cases, X 1 and X 2 may be different.
  • the estimated half-life for hydrolysis of the disiloxane depicted here is 15 days based at pH5 in 90% DMSO/10% water at room temperature based upon NMR experiments. Based on the effect of alkyl group size on silyl ether hydrolysis, the half-life of hydrolysis of the corresponding diphenyltetraethyldisiloxane is expected to be more than ten fold longer. Thus in certain aqueous situations, the hydrolysis of the dimeric disiloxane to monomeric silanol may be essentially irreversible on the timescale relevant for the biological functions they are modulating.
  • the stability of a disiloxane linkage to attack on silicon may be influenced by steric hindrance.
  • Alkyl groups on silicon of increasing size e.g. Me ⁇ Et ⁇ iPr ⁇ tBu
  • Increasing steric hindrance about silicon may relate to homo- or hetero- dimeric designs where Y and X are the connector and ligand/pharmacophore moieties, respectively.
  • Y and X are the connector and ligand/pharmacophore moieties, respectively.
  • -Y-X could be connected through the respective R-groups.
  • the nature of these groups can also influence the stability of the disiloxy dimer and the rate of dimerization to allow one to tune the properties.
  • the incorporation of the silicon in a ring system allows for steric hindrance by flanking substituents rather than directly upon Si.
  • Examples of two disiloxanes are depicted here:
  • selectivity and complementarity can be further increased in designs such as those below where the individual R 2 component in a heterodimeric pairing may be electron-rich and electron-poor aromatic or heteroaromatic rings, such that the result quadrupole interactions stabilize the alignment and association of monomers, and promote the dimerization of hindered silanols to the disiloxane (e.g. where R 3 substituents are electron withdrawing, producing a group like C 6 F 5 , while R 4 may be electron donating or H for a simple phenyl).
  • R 3 substituents are electron withdrawing, producing a group like C 6 F 5
  • R 4 may be electron donating or H for a simple phenyl.
  • other donor-acceptor interactions such as cation (e.g. aminium)/aromatic systems may be
  • a monomer may comprise a connector that joins the ligand moiety with the linker element.
  • such connectors do not have significant binding or other affinity to an intended target.
  • a connector may contribute to the affinity of a ligand moiety to a target.
  • a connector element may be used to connect the linker element to the ligand moiety.
  • the connector element may be used to adjust spacing between the linker element and the ligand moiety.
  • the connector element may be used to adjust the orientation of the linker element and the ligand moiety.
  • the spacing and/or orientation the linker element relative to the ligand moiety can affect the binding affinity of the ligand moiety (e.g., a pharmacophore) to a target.
  • connectors with restricted degrees of freedom are preferred to reduce the entropic losses incurred upon the binding of a multimer to its target biomolecule.
  • connectors with restricted degrees of freedom are preferred to promote cellular permeability of the monomer.
  • the connector element may be used for modular assembly of monomers.
  • a connector element may comprise a functional group formed from reaction of a first and second molecule.
  • a series of ligand moieties may be provided, where each ligand moiety comprises a common functional group that can participate in a reaction with a compatible functional group on a linker element.
  • the connector element may comprise a spacer having a first functional group that forms a bond with a ligand moiety and a second functional group that forms a bond with a linker element.
  • Contemplated connectors may be any acceptable (e.g. pharmaceutically and/or chemically acceptable) bivalent linker that, for example, does not interfere with multimerization of the disclosed monomers.
  • linkers may be substituted or unsubstituted C 1 -C 10 alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, acyl, sulfone, sulfonamide, phosphate, ester, carbonate, carbamate, or amide.
  • Contemplated connectors may include polymeric connectors, such a polyethylene glycol or other pharmaceutically acceptable polymers.
  • a connector may be from about 7 atoms to about 13 atoms in length, or about 8 atoms to about 12 atoms, or about 9 atoms to about 11 atoms in length.
  • a connecter group is from about 6 ⁇ to about 15 ⁇ in length.
  • a multimeric compound for use in a method of treating a patient in need thereof comprises administering to the patient thereof an amount of the first monomer and an amount of the second monomer in amounts effective such that the pharmaceutically effective amount of the resulting multimer is formed in vivo .
  • the multimer may be a dimer.
  • the multimer may be a trimer.
  • a first monomer and a second monomer may be administered substantially sequentially. In other disclosures, the first monomer and the second monomer are administered substantially simultaneously. In some disclosures the monomers may be administered, sequentially or simultaneously, by different routes of administration. In still further disclosures, a first monomer and a second monomer may be administered after forming a multimer.
  • a non-therapeutic method of modulating two or more target biomolecule domains substantially simultaneously comprises contacting an aqueous composition comprising said biomoleular target domain with a first monomer represented by: X 1 -Y 1 -Z 1 (Formula I), and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein X 1 is a first ligand moiety capable of binding to and modulating a first target biomolecule domain; and a second monomer represented by: X 2 -Y 2 -Z 2 (Formula II), and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein X 2 is a ligand moiety capable of binding to and modulating a second target biomolecule domain; wherein upon contact with the aqueous composition, said first monomer and said second monomer forms a multimer that bind
  • a first monomer and a second monomer for use in a method of treating a disease associated with two or more target biomolecules in a patient in need thereof comprises administering to said patient a first monomer represented by: X 1 -Y 1 -Z 1 (Formula I), and pharmaceutically acceptable salts, stereoisomers, metabolites and hydrates thereof, wherein X 1 is a first ligand moiety capable of binding to and modulating a first target biomolecule domain; and administering to said patient a second monomer represented by: X 2 -Y 2 -Z 2 (Formula II), wherein X 2 is a second ligand moiety capable of binding to and modulating a second target biomolecule domain, wherein upon administration, said first monomer and said second monomer forms a multimer in vivo that binds to the first target biomolecule domain and the second target biomolecule domain.
  • the target biomolecule may be a protein.
  • the target biomolecule may be a protein domain.
  • the target biomolecule may be nucleic acid.
  • the ligand moiety e.g., ligand moiety
  • the ligand moiety may be a pharmacophore.
  • a multimer may be used to inhibit or facilitate protein-protein interactions.
  • a multimer may be capable of activating or inactivating a signaling pathway.
  • a multimer may bind to a target protein and affect the conformation of the target protein such that the target protein is more biologically active as compared to when the multimer does not bind the target protein.
  • monomers may be chosen such that a multimer formed from the monomers binds to at least two regions of a target molecule.
  • the compounds may be selected from the group consisting of: (4-(3 -(aminomethyl)phenyl)piperidin-1 -yl)(4-((hydroxydimethylsilyl)methoxy)-phenyl)methanone; N-(4-(4-(3-(aminomethyl)phenyl)-piperidine-1-carbonyl)-2-chlorophenyl)-2-(hydroxydimethylsilyl)acetamide; N-(3-(4-(3-(aminomethyl)phenyl)piperidine-1-carbonyl)-phenyl)-2-(hydroxydimethylsilyl)acetamide; (4-(3-(aminomethyl)phenyl)piperidin-1-yl)(3-chloro-4-((hydroxydimethylsilyl)methoxy)-phenyl)methanone; (4-(3-(aminomethyl)phenyl)-piperidin-1-yl)(3-((amino
  • protein-protein and protein-nucleic acid recognition often work through protein interaction domains, such as the SH2, SH3, and PDZ domains.
  • protein interaction domains such as the SH2, SH3, and PDZ domains.
  • SH2 domains are miniature receptors for protein regions containing a phosphorylated tyrosine.
  • SH2 domains may be found in proteins that act as, or play a role in, for example, adaptors, scaffolds, kinases, phosphatases, ras signalling, transcription, ubiquitination, cytoskeletal regulation, signal regulation, and phospholipid second messenger signaling.
  • SH3 domains bind peptide loops with the motif RXXK or PXXP.
  • Many proteins have both SH2 and SH3 domains, which act as "receptors" to bind one or more protein partners.
  • Coferons may be designed to inhibit binding of a phosphotyrosine protein to its cognate SH2 domain.
  • monomers and multimers may be designed so one ligand binds one motif (i.e. SH2), and a second ligand moiety binds a second motif (i.e. SH3), either on the same or different proteins.
  • linker elements may be used to bring together two pharmacophores on the same target to: (i) bind the target with higher affinity; (ii) exhibit a stronger inhibition than either pharmacophore alone; (iii) exhibit greater activation than either pharmacophore alone; or (iv) create a binding entity covering a larger surface area of the target, making it harder for the organism/cell/virus to develop resistance to the drug via point mutations.
  • a multimer may target a tryptase.
  • a multimer may be used to treat conditions activated by a trypase, such as mast cell mediated inflammatory conditions (e.g. asthma).
  • mast cell mediated inflammatory conditions e.g. asthma
  • Asthma is frequently characterized by progressive development of hyper-responsiveness of the trachea and bronchi to both immunospecific allergens and generalized chemical or physical stimuli, which lead to the onset of chronic inflammation.
  • Leukocytes containing IgE receptors notably mast cells and basophils, are present in the epithelium and underlying smooth muscle tissues of bronchi. These leukocytes initially become activated by the binding of specific inhaled antigens to the IgE receptors and then release a number of chemical mediators. For example, degranulation of mast cells leads to the release of proteoglycans, peroxidase, arylsulfatase B, chymase, and tryptase, which results in
  • Human mast cell ⁇ -tryptase-II is a tetrameric serine protease that is concentrated in mast cell secretory granules.
  • the enzyme is involved in IgE-induced mast cell degranulation in an allergic response and is potentially a target for the treatment of allergic asthma, rhinitis, conjunctivitis and dermatitis.
  • Tryptase has also been implicated in the progression of renal, pulmonary, hepatic, testicular fibrosis, chronic obstructive pulmonary disease (COPD) and inflammatory conditions such as ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, and various other mast cell-related diseases.
  • COPD chronic obstructive pulmonary disease
  • multimers may be used to treat such diseases.
  • Tryptase is stored in the mast cell secretory granules and is the major protease of human mast cells. Tryptase has been implicated in a variety of biological processes, including degradation of vasodilatory and bronchodilatory neuropeptides and modulation of bronchial responsiveness to histamine.
  • tryptase inhibitors may be useful as antiinflammatory agents for treatment of inflammatory disease and may also be useful in treating or preventing allergic rhinitis, inflammatory bowel disease, psoriasis, ocular or vernal or ulcerative conjunctivitis, dermatological conditions (e.g., psoriasis, eczema, or atopic dermatitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis, hematoid arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, or gouty arthritis), rheumatoid spondylitis, interstitial lung disease, chronic obstructive pulmonary disease, and diseases of joint cartilage destruction.
  • dermatological conditions e.g., psoriasis, eczema, or atopic dermatitis
  • arthritis e.g., rheumatoid arthritis, osteoarthritis, hemato
  • tryptase inhibitors may be useful in treating or preventing fibrotic conditions, for example, fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas, hepatic fibrosis, renal fibrosis, testicular, and hypertrophic scars.
  • tryptase inhibitors may be useful in treating or preventing myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture.
  • tryptase has also been discovered to activate prostromelysin that in turn activates collagenase, thereby initiating the destruction of cartilage and periodontal connective tissue, respectively.
  • tryptase inhibitors may be useful in the treatment or prevention of arthritis, periodontal disease, diabetic retinopathy, a condition relating to atherosclerotic plaque rupture, anaphylatis ulcerative colitis, and tumour growth.
  • tryptase inhibitors may be useful in the treatment of anaphylaxis, multiple sclerosis, peptic ulcers, and syncytial viral infections.
  • a variety of antibiotics elicit their antibacterial activity by binding to the bacterial ribosome and inhibiting protein synthesis. Many of these antibiotics bind the peptidyl transferase center of the ribosome (P site).
  • a multimer may bind to two or more sites on the ribosome. For example, a first pharmacophore of a multimer may bind to the peptidyl transferase center of the ribosome (i.e., the P site) and a second multimer may bind to site adjacent to the P site.
  • Linezolid an oxazolidinone antibiotic, is believed to bind adjacent to the binding site for Sparsomycin.
  • target protein families are provided in Table 1 below. Also provided in Table 1 are endogenous ligands, agonists, and antagonists that bind to the protein families. Examples of detection assays are also provided in Table 1, which may be used in a screening assay to detect activation and/or inhibition of the target protein.
  • Table 2 Provided in Table 2 are non-limiting examples of domains that can bind a ligand, proteins that contain the domains, known inhibitors, and K D values of binding partners (i.e., ligands). Examples of detection assays are also provided in Table 2, which may be used in a screening assay to find ligands for the domains.
  • a pharmacophore is typically an arrangement of the substituents of a moiety that confers biochemical or pharmacological effects.
  • identification of a pharmacophore may be facilitated by knowing the structure of the ligand in association with a target biomolecule.
  • pharmacophores may be moieties derived from molecules previously known to bind to target biomolecules (e.g., proteins), fragments identified, for example, through NMR or crystallographic screening efforts, molecules that have been discovered to bind to target proteins after performing high- throughput screening of natural products libraries, previously synthesized commercial or non-commercial combinatorial compound libraries, or molecules that are discovered to bind to target proteins by screening of newly synthesized combinatorial libraries. Since most pre-existing combinatorial libraries are limited in the structural space and diversity that they encompass, newly synthesized combinatorial libraries may include molecules that are based on a variety of scaffolds.
  • pharmacophores may be derived from traditional approaches such as fragment based drug design and structure based drug design.
  • any pharmacophore including pre-existing pharmacophores such as approved drugs are amenable to be designed as monomers through the incorporation of the appropriate linker elements and connector elements.
  • previously approved drugs that have poor efficacy due to a low affinity for a first macromolecular target may be utilized as a pharmacophore component of a first monomer which when combined with a pharmacophore of a second monomer that also binds the first macromolecular target or a second macromolecular target that interacts with the first macromolecular target results in enhanced binding and, in some cases, higher efficacy.
  • previously approved drugs that have low efficacy as a result of size, molecular weight or other physicochemical attributes that reduce the cellular uptake of the drug may be amenable to being converted into one or more monomers that bear the appropriate pharmacophoric elements, such that each monomer has physicochemical attributes that allow for increased cellular uptake.
  • a ligand moiety (e.g., a pharmacophore) may have a molecular weight between 50 Da and 2000 Da, in some disclosures between 50 Da and 1500 Da, in some disclosures, between 50 Da and 1000 Da, and in some disclosures, between 50 Da and 500 Da. In certain disclosures, a ligand moiety may have a molecular weight of less than 2000 Da, in some disclosures, less than 1000 Da, and in some disclosures less than 500 Da.
  • the compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein.
  • compositions may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
  • a compound may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.
  • Treatment can be continued for as long or as short a period as desired.
  • the compositions may be administered on a regimen of, for example, one to four or more times per day.
  • a suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely.
  • a treatment period can terminate when a desired result, for example a partial or total alleviation of symptoms, is achieved.
  • the present disclosure provides pharmaceutical compositions comprising monomers, dimers, and/or multimers as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • Exemplary pharmaceutical compositions may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which contains one or more of the compounds, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may be mixed with a pharmaceutical carrier, e . g ., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e . g ., water, to form a solid preformulation composition containing a homogeneous mixture of a compound, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e . g ., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e . g ., water
  • a pharmaceutical carrier e . g ., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, tal
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions and compounds may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
  • compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants
  • IEnteral pharmaceutical formulations including a disclosed pharmaceutical composition comprising monomers, dimers, and/or multimers, an enteric material; and a pharmaceutically acceptable carrier or excipient thereof are disclosed.
  • Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
  • the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum.
  • the pH of the duodenum is about 5.5
  • the pH of the jejunum is about 6.5
  • the pH of the distal ileum is about 7.5.
  • enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
  • Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleat, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins
  • kits containing one or more compositions each including the same or different monomers.
  • Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to treat a disease or condition. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • Such kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, ... etc.... Second Week, Monday, Tuesday, etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • compositions for use in various methods that include additional active agents, or administering additional active agents.
  • compositions that include additional active agents, or administering additional active agents.
  • the compounds, as described herein may be substituted with any number of substituents or functional moieties.
  • substituted whether preceded by the term “optionally” or not, and substituents contained in formulas, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • the substituent when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • Non-limiting examples of substituents include acyl; aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy; heterocyclylalkoxy; heterocyclyloxy; heterocyclyloxyalkyl; alkenyloxy; alkynyloxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; oxo; -F; -Cl; -Br; -I; -OH; -NO 2 ; -CN; -SCN; -SR x ; - CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; -CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 SO 2 CH 3 ; -OR x , -C(O)R
  • combinations of substituents and variables described herein may be preferably those that result in the formation of stable compounds.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • an acyl group refers to a moiety that includes a carbonyl group.
  • an acyl group may have a general formula selected from - C(O)R x ; -CO 2 (R x ); -C(O)N(R x ) 2 ; -OC(O)R x ; -OCO 2 R x ; and -OC(O)N(R x ) 2 ; wherein each occurrence of R x independently includes hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be
  • aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
  • aliphatic is intended herein to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
  • heteroaliphatic refers to aliphatic moieties that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be branched, unbranched, cyclic or acyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
  • heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including acyl; aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy; heterocyclylalkoxy; heterocyclyloxy; heterocyclyloxyalkyl; alkenyloxy; alkynyloxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; oxo; -F; -Cl; -Br; -I; -OH; - NO 2 ; -CN; -SCN; -SR x ; -CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; -CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH
  • aryl and heteroaryl refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
  • Substituents include any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.
  • heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from the group consisting of S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from the group consisting of S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • aryl and heteroaryl groups can be unsubstituted or substituted, wherein substitution includes replacement of one, two, three, or more of the hydrogen atoms thereon independently with any one or more of the following moieties including: aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; cycloalkoxy; heterocyclylalkoxy; heterocyclyloxy; heterocyclyloxyalkyl; alkenyloxy; alkynyloxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; oxo; -F; -Cl; -Br; -I; -OH; -NO 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; -CH 2 OH; - CH 2 CH 2 OH
  • heterocyclic refers to an aromatic or non-aromatic, partially unsaturated or fully saturated, 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or aromatic heterocyclic groups fused to a non-aromatic ring.
  • heterocyclic rings include those having from one to three heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from the group consisting of O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the group consisting of the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein for example as C 2-6 alkenyl, and C 3-4 alkenyl, respectively.
  • alkenyl groups include vinyl, allyl, butenyl, pentenyl, etc.
  • alkenyloxy refers to a straight or branched alkenyl group attached to an oxygen (alkenyl-O).
  • alkenoxy groups includegroups with an alkenyl group of 3-6 carbon atoms referred to herein as C 3-6 alkenyloxy.
  • alkenyloxy groups include allyloxy, butenyloxy, etc.
  • alkoxy refers to a straight or branched alkyl group attached to an oxygen (alkyl-O-).
  • exemplary alkoxy groups include groups with an alkyl group of 1-6 or 2-6 carbon atoms, referred to herein as C 1-6 alkoxy, and C 2 -C 6 alkoxy, respectively.
  • exemplary alkoxy groups include methoxy, ethoxy, isopropoxy, etc.
  • alkoxycarbonyl refers to a straight or branched alkyl group attached to oxygen, attached to a carbonyl group (alkyl-O-C(O)-).
  • exemplary alkoxycarbonyl groups include alkoxycarbonyl groups of 1-6 carbon atoms, referred to herein as C 1-6 alkoxycarbonyl.
  • Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.
  • alkynyloxy refers to a straight or branched alkynyl group attached to an oxygen (alkynyl-O)).
  • exemplary alkynyloxy groups include propynyloxy.
  • alkyl refers to a saturated straight or branched hydrocarbon, for example, such as a straight or branched group of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C 1-6 alkyl, C 1-4 alkyl, and C 1-3 alkyl, respectively.
  • Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
  • alkylcarbonyl refers to a straight or branched alkyl group attached to a carbonyl group (alkyl-C(O)-).
  • exemplary alkylcarbonyl groups include alkylcarbonyl groups of 1-6 atoms, referred to herein as C 1-6 alkylcarbonyl groups.
  • Exemplary alkylcarbonyl groups include acetyl, propanoyl, isopropanoyl, butanoyl, etc.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-6, or 3-6 carbon atoms, referred to herein as C 2-6 alkynyl, and C 3-6 alkynyl, respectively.
  • exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
  • carbonyl refers to the radical -C(O)-.
  • carboxylic acid refers to a group of formula -CO 2 H.
  • cyano refers to the radical -CN.
  • cycloalkoxy refers to a cycloalkyl group attached to an oxygen (cycloalkyl-O-).
  • cycloalkyl refers to a monocyclic saturated or partially unsaturated hydrocarbon group of for example 3-6, or 4-6 carbons, referred to herein, e.g., as C 3-6 cycloalkyl or C 4-6 cycloalkyl and derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or, cyclopropyl.
  • halo or halogen as used herein refer to F, Cl, Br, or I.
  • heterocyclylalkoxy refers to a heterocyclyl- alkyl-O-group.
  • heterocyclyloxyalkyl refers to a heterocyclyl-O-alkyl- group.
  • heterocyclyloxy refers to a heterocyclyl-O- group.
  • heteroaryloxy refers to a heteroaryl-O- group.
  • hydroxy and "hydroxyl” as used herein refers to the radical -OH.
  • connector refers to an atom or a collection of atoms optionally used to link interconnecting moieties, such as a disclosed linker and a pharmacophore.
  • Contemplated connectors are generally hydrolytically stable.
  • Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
  • “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or a human, as appropriate.
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals ( e.g., dogs, cats, and the like), farm animals ( e . g ., cows, sheep, pigs, horses, and the like) and laboratory animals ( e.g., rats, mice, guinea pigs, and the like).
  • the mammal treated is desirably a mammal in which treatment of obesity, or weight loss is desired.
  • “Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
  • the term "therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician.
  • the compounds are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in weight loss.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p -toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
  • stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “ S ,” depending on the configuration of substituents around the stereogenic carbon atom. Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure.
  • Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated "( ⁇ )" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as geometric isomers, enantiomers or diastereomers.
  • the enantiomers and diastereomers may be designated by the symbols "(+),” "(-).” “ R “ or “ S ,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • Geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds. The symbol ............
  • stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. Various stereoisomers of these compounds and mixtures thereof are encompassed by this disclosure.
  • Individual enantiomers and diasteriomers of the compounds can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using steroselective chemical or enzymatic reagents.
  • Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009 .
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the compound is amorphous.
  • the compound is a polymorph.
  • the compound is in a crystalline form.
  • isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 10 B, and 36 Cl, respectively.
  • a compound may have one or more H atom replaced with deuterium.
  • isotopically-labeled disclosed compounds e . g ., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art.
  • synthetic procedures known in the art.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated.
  • the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed.
  • Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated.
  • the starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.
  • Stock solutions of recominbant human tryptase, beta, from lung were made at 30 ⁇ M, in solution with 50 ⁇ M heparin sulfate and 500mM NaCl.
  • Multimer tryptase inhibitor stock solutions were made at 50mM in DMSO.
  • Drug plates were made at 5 X the final concentration in assay buffer (50mM HEPES, 150mM NaCl, 100 ⁇ M EDTA, pH 7.4, 0.02% Tween-20). A final concentration of 1nM tryptase was used. When required, drugs were diluted in assay buffer immediately before use in 10-fold serial dilutions.
  • the release of fluorescent AMC was immediately measured every 60 seconds over 30-60 minutes at an excitation wavelength of 367 nm, monitoring emission at 468 nm on a Spectramax M5 (Molecular Devices) microplate reader.
  • the Softmax Pro (Molecular Devices) and Graphpad prism software were used to determine V max ,and concentration-response curve IC 50 s, respectively.
  • Monomers with the potential to form heterodimers were evaluated in an in vitro Transcription and Translation assay (TnT assay) using the commercially available E. coli S30 Extract System for Circular DNA kit (Promega Catalog # L1020) according to the manufacturers instructions with minor modifications. Monomers were tested independently to determine individual IC 50 values. Pairs of monomers with the potential to form heterodimers were assayed at concentrations that ranged about their individual IC25 values.
  • Each reaction uses 2 ⁇ l (250ng/ ⁇ l) of the pBESTlucTM DNA based circular luciferase plasmid (Promega Catalog # L492A), with 4 ⁇ l of complete amino acid mix (Promega Catalog # L4461), 13 ⁇ l of S30 Premix Without Amino Acids (Promega Catalog # L512A), 5 ⁇ l of S30 Extract (Promega Catalog # L464A), monomers at the appropriate concentration, and nuclease free water in a total volume of 35 ⁇ l. Assays were carried out in Costar 96 well white round bottom plates.
  • Assay plates were setup with a master mix consisting of S30 extract and water, followed by the addition of compound, with the final addition of a master mix consisting of the plasmid, amino acid mix, and the S30 Premix. Plates were incubated at 37°C for one hour followed by addition of 35 ⁇ l of the Bright-Glo Luciferase Reagent (Promega Catalog # E2620). After removal of 35 ⁇ l of the reaction mixture, the luminescence was recorded immediately in the Spectramax M5 plate reader (Molecular Devices). The data was plotted to generate dose-response curves using GraphPad Prism.
  • IC 50 ranges are provided for various exemplary monomers.
  • the prefix “Target,” as used elsewhere in the Examples, has been shortened to “T.”
  • “Target-14” has been shortened to “T14.”
  • A” refers to an IC 50 range of 0.1 nM to 1 ⁇ M
  • B refers to an IC 50 range of 1 ⁇ M to 10 ⁇ M
  • C refers to an IC 50 range of 10 ⁇ M to 65 ⁇ M.
  • Desired halo aryl carboxylic acids were first coupled with tert -butyl 3-(piperidin-4-yl) benzylcarbamate and coupled product was reacted with 1,2-diethoxy-1,1,2,2-tetramethyldisilane to get ethoxydimethyl(Aryl)silanes, which upon treatment with acetic acid and subsequent treatment with TFA resulted in the title compounds.
  • These compounds as well as their N -Boc precursors were found to be in the form of mixture of monomer and dimer in HPLC/LCMS analysis.
  • Vinylic analogue of this compound was synthesized by reaction of Boc Deprotected B-47 with dimethyl ethoxy vinyl silane in presence of Pd (II) acetate & Tri (O-tolyl) phosphine in DMF using sodium acetate as a base (Scheme-2).
  • TFA salts were converted to hydrochloride salts by stirring with 2N HCl for 30 min under nitrogen atmosphere followed by lyophilization.
  • Approach-1 Desired halo aryl carboxylic acids were first coupled with protected 4-(3-Aminomethyl phenyl) piperidine or 5-Aminomethyl Spiro [benzofuran-3, 4'-piperidine]. Coupled product was reacted with 1,2-diethoxy-1,1,2,2-tetramethyldisilane to get ethoxydimethyl(Aryl)silanes, which upon treatment with acetic acid and subsequent deprotection afforded in the title compounds. 11 compounds were synthesized from Approach-1.
  • Step-1 A stirred solution of methyl-3-hydroxy benzoate (1 g, 6.578 mmol) in acetone (30 mL) and potassium carbonate (2.72 g, 19.7 mmol) was stirred at room-temperature for 15min and then charged with chloromethyl dimethyl methoxy silane (1.4 mL, 9.8 mmol) and heated to 60 0 C for 72hrs. The solvent was concentrated in vacuo and diluted with water (20 mL) and extracted with ethyl acetate (3x25 mL).
  • Step-1 Coupling of the aryl bromo carboxylic acids (Al) was carried out with appropriate protected core as shown in the synthetic scheme as per conditions mentioned in the table below.
  • Analytical data A-62 tert -butyl-3-(piperidin-4-yl) benzyl carbamate, (1.2 eq.), EDCI (1.5 eq.) DMAP (0.5 eq.), DCM (5ml) R.T. 12 h; Yield: 59% Mol.
  • Reaction mixture was diluted with water, filtered through celite, extracted with ethyl acetate and the combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to get the crude products which were sufficiently pure to be used for silylation.
  • Step-1 Bromo Esters were synthesized from the Bromo carboxylic acids (A1) detailed description given above as per conditions mentioned in the table. Details of the compounds synthesized are as below Comp. No. Structure Brief Reaction conditions Analytical data D-52 thionyl chloride (1.2 eq), ethanol, 60°C, 5 hrs. Yield 70.5%. Mol.
  • Reaction mixture was then diluted with water, filtered through celite, extracted with ethyl acetate and ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to get the crude products which were sufficiently pure to be used for next step.
  • Bromo esters were synthesized by esterification of corresponding bromo acids by refluxing with alcohol and thionyl chloride.
  • the details of bromo acids sourced/synthesised as per literature methods/synthesised by adapted methods are given below Comp. No. Structure Brief Reaction conditions
  • Analytical data E-52 1,2-diethoxy-1,1-2,2-tetarmethyl silane (3 eq.), PdCl2 (0.1 eq),DTBPBP (0.2 eq), DIPEA (6 eq), NMP, 50°C, 14 hrs. Yield 44.5%. Mol.
  • Approach-1 Desired halo aryl carboxylic acids were first coupled with protected 4-(3-Aminomethyl phenyl) piperidine or 5-Aminomethyl Spiro [benzofuran-3, 4'-piperidine]. Coupled product was reacted with 1,2-diethoxy-1,1,2,2-tetramethyldisilane to get ethoxydimethyl(Aryl)silanes, which upon treatment with acetic acid and subsequent deprotectionafforded in the title compounds. 11 compounds were synthesized from Approach-1. A1-148 3-bromobenzofuran-5-carboxylic acid 1) US2003/232853; (2003 ) 2) J.Med. Chem, 38; (1995); 3094 - 3105 3) US2011/82098
  • Step-1 Coupling of the aryl bromo carboxylic acids (A1) was carried out with appropriate protected core as shown in the synthetic scheme as per conditions mentioned in the table below.
  • Reaction mixture was diluted with water, filtered through celite, extracted with ethyl acetate and the combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to get the crude products which were sufficiently pure to be used for deprotection.
  • Table 10 contains exemplary compounds. One of ordinary skill in the art will recognize that these compounds may be used to form homodimic or heterodimeric compounds. TABLE 10. Exemplary Silyl Monomers Targeted to Tryptase. Sr. No. Cmpd. Structure Cmpd.
  • T130 2 T46-vinyl 3 T48-vinyl 4 T50 5 T51 6 T52 7 T121 8 T122 9 T93 10 T94 11 T129 12 T62 silyl 13 T116 silyl 14 T120 15 T128 16 T148 17 18 T149 19 20 21 22 23 24 25 26 27 T11 Silyl 28 29 30 31 32 33 34 35 T35Silyl 36 T152NMeth yl 37 T152 38 T32Silyl 39 T52Spiro 40 T120F 41 T137 42 T138 43 T129Spiro 44 T129Smeth yl 45 T148-spiro 46 T52-spiro 47 T129-spiro 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 R -alkyl-aryl, -alkyl-heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl, -alkynyl-aryl,
  • R -alkyl-aryl, - alkyl-heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl, -alkynyl-aryl, -alkynyl-heteroaryl, phenyl, heteroaryl, where phenyl and heteroaryl can be optionally substituted by halogen, -CN, - OR, -SR, phenyl, or heteroaryl where phenyl or heteroaryl can be optionally substituted by halogen, cyano, hydroxyl.
  • R -alkyl-aryl, - alkyl-heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl, -alkynyl-aryl, -alkynyl-heteroaryl, phenyl, heteroaryl, where phenyl and heteroaryl can be optionally substituted by halogen, -CN, - OR, -SR, phenyl, or heteroaryl where phenyl or heteroaryl can be optionally substituted by halogen, cyano, hydroxyl.
  • Table 11 contains exemplary compounds that target to the ribosome. In some embodiments, these compounds form heterodimeric compounds. TABLE 11. Exemplary Silyl Monomers Targeted to the Ribosome. Sr. No. Cmpd. Structure Cmpd. Code 1 2 3 4 AzSi-1 5 Cl-Ph-Si-meta 6 LZN-Si-3 7 FFL-Si-3
  • Table 12 contains exemplary ligand moieties (i.e., X 1 , X 2 , or X 3 , and the like), where indicates the attachment point to a connector moiety (i.e., Y 1 , Y 2 , or Y 3 , and the like) or a silyl moiety (i.e., Z 1 , Z 2 , or Z 3 , and the like) if the connector moiety is absent.

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Claims (11)

  1. Composé multimère formé par multimérisation dans un milieu aqueux d'un premier monomère représenté par :

            X1-Y1-Z1     (Formule I)

    et les sels, stéréoisomères et hydrates pharmaceutiquement acceptables de celui-ci,
    et d'un deuxième monomère représenté par :

            X2-Y2-Z2     (Formule II)

    et les sels, stéréoisomères et hydrates pharmaceutiquement acceptables de celui-ci,
    où
    X1 est un premier fragment ligand capable de se lier à et de moduler une première biomolécule cible ;
    Y1 est absent ou est un fragment connecteur lié de façon covalente à X1 et Z1 ;
    X2 est un deuxième fragment ligand capable de se lier à et de moduler une deuxième biomolécule cible ;
    Y2 est absent ou est un fragment connecteur lié de façon covalente à X2 et Z2 ;
    Z1 et Z2, indépendamment, pour chaque occurrence, sont choisis dans le groupe constitué par :
    Figure imgb0258
     où
    W1, indépendamment, pour chaque occurrence, est (a) absent ; ou (b) choisi dans le groupe constitué par l'alkyle en C1-4, le -O-alkyle en C1-4, l'alkyle en C1-4-C(O)-, le -C(O)-alkyle en C1-4, le -N(Ra)-alkyle en C1-4, l'alkyle en C1-4-O-C(O)-, le -C(O)-O-alkyle en C1-4, le -NRa-C(O)-, l'alcényle en C2-6, l'alcynyle en C2-6, le cycloalkyle en C3-6, le phényle, l'hétéroaryle et l'hétérocyclique ; où l'alkyle en C1-4, l'alcényle en C2-6, l'alcynyle en C2-6, le cycloalkyle en C3-6, le phényle, l'hétérocyclique et l'hétéroaryle sont facultativement substitués indépendamment, pour chaque occurrence, par un, deux, trois ou davantage de substituants choisis dans le groupe constitué par l'alkyle en C1-4, l'alcényle en C2-6, l'alcynyle en C2-6, l'alcoxy en C1-4, le -C(O)-alkyle en C1-6, le -C(O)-O-alkyle en C1-4, le cycloalkyle, l'hétérocyclique, le phényle, l'hétéroaryle, l'halogène, l'hydroxyle, le nitrosulfoxyde, la sulfone, le sulfonamide et le cyano, où le fragment cycloalkyle, hétérocyclique, phényle ou hétéroaryle est facultativement substitué par un, deux, trois ou davantage de substituants choisis dans le groupe constitué par l'halogène, l'amino, le cyano, l'hydroxyle, l'alkyle en C1-6, le phényle, l'hétéroaryle et l'amino ;
    Q1 est -SH ou -OH ;
    Ra et Rb sont indépendamment choisis, pour chaque occurrence, dans le groupe constitué par l'hydrogène, l'alkyle en C1-4, le -O-alkyle en C1-4 et le -NH-alkyle en C1-4 ; où l'alkyle en C1-4 peut être facultativement substitué par un ou plusieurs substituants choisis dans le groupe constitué par l'halogène, le cyano, l'oxo et l'hydroxyle ; ou
    Ra et Rb, conjointement avec l'azote auquel ils sont fixés, peuvent former un noyau hétérocyclique à 4 à 7 chaînons, qui peut avoir un ou plusieurs hétéroatomes supplémentaires choisis parmi O, S ou N ; où le noyau hétérocyclique à 4 à 7 chaînons peut être facultativement substitué par un ou plusieurs substituants choisis dans le groupe constitué par l'halogène, le cyano, l'oxo, l'amino et l'hydroxyle ;
    R1 et R2 sont indépendamment choisis, pour chaque occurrence, dans le groupe constitué par-OH, l'alkyle en C1-6, le -O-alkyle en C1-6, l'alcényle en C2-6, le cycloalkyle en C3-6, l'alkyle en C1-6-NRaRb, le phényle et l'hétéroaryle ; où l'alkyle en C1-6, l'alcényle en C2-6, le cycloalkyle en C3-6, Ra, Rb, le phényle et l'hétéroaryle, indépendamment choisis, pour chaque occurrence, peuvent être facultativement substitués par un ou plusieurs substituants choisis dans le groupe constitué par l'halogène, le cyano, l'hydroxyle, l'amino, l'alkyle en C1-6, l'hétéroaryle et le phényle ; ou R1 et R2, conjointement avec le silicium auquel ils sont fixés, peuvent former un noyau hétérocyclique à 5 à 8 chaînons, qui peut avoir un ou plusieurs hétéroatomes supplémentaires choisis parmi O, S ou N ; où le noyau hétérocyclique à 5 à 8 chaînons peut être facultativement substitué par un ou plusieurs substituants choisis dans le groupe constitué par l'halogène, le cyano, l'oxo, l'amino et l'hydroxyle ;
    BB, indépendamment pour chaque occurrence, est un fragment cycloalkyle, hétérocyclique, aryle ou hétéroaryle à 4 à 7 chaînons, où le fragment cycloalkyle, hétérocyclique, aryle ou hétéroaryle est facultativement substitué par un, deux, trois ou davantage de groupes représentés par RBB ;
    chaque RBB est indépendamment choisi, pour chaque occurrence, dans le groupe constitué par l'hydrogène, l'halogène, le nitro, le cyano, l'hydroxyle, l'amino, le thio, -COOH, -CONHR', le noyau aliphatique substitué ou non substitué, le noyau hétéroaliphatique substitué ou non substitué, l'alkyle en C1-4, le -O-alkyle en C1-4, le -N(Ra)-alkyle en C1-4, le -C(O)-alkyle en C1-4, le -C(O)-O-alkyle en C1-4, le -C(O)-NRaRb, l'alcényle en C2-6, l'alcynyle en C2-6, le cycloalkyle en C3-6, l'hétérocyclique, le phényle, le phénoxy, l'hétéroaryle, l'alkylène en C1-4-phényle, l'alkylène en C1-4-hétéroaryle, l'alkylène en C1-4-hétérocyclyle, l'alcénylène en C2-6-phényle, l'alcénylène en C2-6-hétéroaryle, l'alcénylène en C2-6-hétérocyclyle, l'alcynyle en C2-6-phényle, l'alcynyle en C2-6-hétéroaryle, l'alcynyle en C2-6-hétérocyclyle ; où l'alkyle en C1-4, l'alcényle en C2-6, l'alcynyle en C2-6, le cycloalkyle en C3-6, le phényle, le phénoxy, l'hétérocyclyle et l'hétéroaryle sont facultativement substitués par un, deux, trois ou davantage de substituants choisis dans le groupe constitué par l'alkyle en C1-4, l'alcoxy en C1-4, le -C(O)alkyle en C1-4, le - C(O)-O-alkyle en C1-4, le -C(O)-NRaRb, l'halogène, le cyano, l'hydroxyle, le cycloalkyle, l'hétérocyclique, le phényle ou l'hétéroaryle ; et
    R' est indépendamment choisi, pour chaque occurrence, dans le groupe constitué par l'hydrogène, le noyau aliphatique substitué ou non substitué et le noyau hétéroaliphatique substitué ou non substitué.
  2. Composé multimère selon la revendication 1, dans lequel X1 et X2 sont identiques.
  3. Composé multimère selon la revendication 1, dans lequel X1 et X2 sont différents.
  4. Composé multimère selon l'une quelconque des revendications 1 à 3, dans lequel Z1 et Z2, indépendamment pour chaque occurrence, sont :
    Figure imgb0259
     où
    RBB est indépendamment choisi, pour chaque occurrence, dans le groupe constitué par l'hydrogène, l'halogène, le nitro, le cyano, l'hydroxyle, l'amino, le thio, -COOH, -CONHR', le noyau aliphatique substitué ou non substitué et l'hétéroaliphatique substitué ou non substitué ;
    W1, indépendamment choisi pour chaque occurrence, est (a) absent ou (b) de l'alkylène en C1-4 ; et
    R1 et R2, indépendamment, pour chaque occurrence, sont de l'alkyle en C1-6.
  5. Composé multimère selon la revendication 4, représenté par :
    Figure imgb0260
  6. Composé multimère représenté par :
    un première monomère et un deuxième monomère reliés par une liaison disiloxane covalente, où le premier monomère est représenté par X1-Y1-Z1 (Formule I) et les sels, stéréoisomères et hydrates pharmaceutiquement acceptables de celui-ci, et le deuxième monomère est représenté par X2-Y2-Z2 (Formule II) et les sels, stéréoisomères et hydrates pharmaceutiquement acceptables de celui-ci ;
    où
    X1 est un premier fragment ligand capable de se lier à et de moduler une première biomolécule cible ;
    Y1 est absent ou est un fragment connecteur lié de façon covalente à X1 et Z1 ;
    X2 est un deuxième fragment ligand capable de se lier à et de moduler une deuxième biomolécule cible ;
    Y2 est absent ou est un fragment connecteur lié de façon covalente à X2 et Z2 ; et
    Z1 et Z2, indépendamment, pour chaque occurrence, sont choisis dans le groupe constitué par :
    Figure imgb0261
     où
    W1 est absent ;
    Q1 est -OH ;
    R1 et R2 sont indépendamment choisis, pour chaque occurrence, dans le groupe constitué par -OH, l'alkyle en C1-6, le -O-alkyle en C1-6, l'alcényle en C2-6, le cycloalkyle en C3-6, l'alkyle en C1-6-NRaRb, le phényle et l'hétéroaryle ; où l'alkyle en C1-6, l'alcényle en C2-6, le cycloalkyle en C3-6, Ra, Rb, le phényle et l'hétéroaryle, indépendamment choisis, pour chaque occurrence, peuvent être facultativement substitués par un ou plusieurs substituants choisis dans le groupe constitué par l'halogène, le cyano, l'hydroxyle, l'amino, l'alkyle en C1-6, l'hétéroaryle et le phényle ;
    Ra et Rb sont indépendamment choisis, pour chaque occurrence, dans le groupe constitué par l'hydrogène, l'alkyle en C1-4, le -O-alkyle en C1-4 et le -NH-alkyle en C1-4 ; où l'alkyle en C1-4 peut être facultativement substitué par un ou plusieurs substituants choisis dans le groupe constitué par l'halogène, le cyano, l'oxo et l'hydroxyle ; ou
    Ra et Rb, conjointement avec l'azote auquel ils sont fixés, peuvent former un noyau hétérocyclique à 4 à 7 chaînons, qui peut avoir un ou plusieurs hétéroatomes supplémentaires choisis parmi O, S ou N ; où le noyau hétérocyclique à 4 à 7 chaînons peut être facultativement substitué par un ou plusieurs substituants choisis dans le groupe constitué par l'halogène, le cyano, l'oxo, l'amino et l'hydroxyle ;
    BB, indépendamment pour chaque occurrence, est un fragment cycloalkyle, hétérocyclique, aryle ou hétéroaryle à 4 à 7 chaînons, où le fragment cycloalkyle, hétérocyclique, aryle ou hétéroaryle est facultativement substitué par un, deux, trois ou davantage de groupes représentés par RBB ;
    chaque RBB est indépendamment choisi, pour chaque occurrence, dans le groupe constitué par l'hydrogène, l'halogène, le nitro, le cyano, l'hydroxyle, l'amino, le thio, -COOH, -CONHR', le noyau aliphatique substitué ou non substitué, le noyau hétéroaliphatique substitué ou non substitué, l'alkyle en C1-4, le -O-alkyle en C1-4, le -N(Ra)-alkyle en C1-4, le -C(O)-alkyle en C1-4, le -C(O)-O-alkyle en C1-4, le -C(O)-NRaRb, l'alcényle en C2-6, l'alcynyle en C2-6, le cycloalkyle en C3-6, l'hétérocyclique, le phényle, le phénoxy, l'hétéroaryle, l'alkylène en C1-4-phényle, l'alkylène en C1-4-hétéroaryle, l'alkylène en C1-4-hétérocyclyle, l'alcénylène en C2-6-phényle, l'alcénylène en C2-6-hétéroaryle, l'alcénylène en C2-6-hétérocyclyle, l'alcynyle en C2-6-phényle, l'alcynyle en C2-6-hétéroaryle, l'alcynyle en C2-6-hétérocyclyle ; où l'alkyle en C1-4, l'alcényle en C2-6, l'alcynyle en C2-6, le cycloalkyle en C3-6, le phényle, le phénoxy, l'hétérocyclyle et l'hétéroaryle sont facultativement substitués par un, deux, trois ou davantage de substituants choisis dans le groupe constitué par l'alkyle en C1-4, l'alcoxy en C1-4, le -C(O)alkyle en C1-4, le - C(O)-O-alkyle en C1-4, le -C(O)-NRaRb, l'halogène, le cyano, l'hydroxyle, le cycloalkyle, l'hétérocyclique, le phényle ou l'hétéroaryle ; et
    R' est indépendamment choisi, pour chaque occurrence, dans le groupe constitué par l'hydrogène, le noyau aliphatique substitué ou non substitué et le noyau hétéroaliphatique substitué ou non substitué.
  7. Composé multimère selon la revendication 6, dans lequel le premier monomère et le deuxième monomère sont différents.
  8. Composé multimère selon la revendication 6, dans lequel le premier monomère et le deuxième monomère sont identiques.
  9. Composé multimère selon l'une quelconque des revendications 6 à 8, dans lequel Z1 et Z2, indépendamment pour chaque occurrence, sont :
    Figure imgb0262
     où
    RBB est indépendamment choisi, pour chaque occurrence, dans le groupe constitué par l'hydrogène, l'halogène, le nitro, le cyano, l'hydroxyle, l'amino, le thio, -COOH, -CONHR', le noyau aliphatique substitué ou non substitué et l'hétéroaliphatique substitué ou non substitué ;
    W1, indépendamment choisi pour chaque occurrence, est (a) absent ou (b) de l'alkylène en C1-4 ; et
    R1 et R2, indépendamment, pour chaque occurrence, sont de l'alkyle en C1-6.
  10. Composé multimère selon la revendication 9, représenté par :
    Figure imgb0263
  11. Composé choisi dans le groupe constitué par : la (4-(3-(aminométhyl)phényl)pipéridin-1-yl)(4-((hydroxydiméthylsilyl)méthoxy)phényl)méthanone ; le N-(4-(4-(3-(aminométhyl)phényl)-pipéridine-1-carbonyl)-2-chlorophényl)-2-(hydroxydiméthylsilyl)acétamide ; le N-(3-(4-(3-(aminométhyl)phényl)pipéridine-1-carbonyl)phényl)-2-(hydroxydiméthylsilyl)acétamide ; la (4-(3-(aminométhyl)phényl)pipéridin-1-yl)(3-chloro-4-((hydroxydiméthylsilyl)méthoxy)-phényl)méthanone ; la (4-(3-(aminométhyl)phényl)pipéridin-1-yl))(3-((hydroxydiméthylsilyl)-méthoxy)phényl)méthanone ; la (4-(3-(aminométhyl)phényl)pipéridin-1-yl)(3-chloro-5-((hydroxydiméthylsilyl)méthoxy)phényl)méthanone ; le N-(4-(4-(3-(aminométhyl)phényl)-pipéridine-1-carbonyl)phényl)-2-(hydroxydiméthylsilyl)acétamide ; et les sels, stéréoisomères et hydrates de ceux-ci.
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EP2693883B1 (fr) * 2011-04-07 2018-12-26 Cornell University Monomères silyles aptes à former un multimère dans une solution aqueuse et leurs procédés d'utilisation
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MA48709A (fr) 2015-05-12 2020-04-08 Blinkbio Inc Conjugués de médicament à base de silicium et leurs procédés d'utilisation
AR106515A1 (es) 2015-10-29 2018-01-24 Bayer Cropscience Ag Sililfenoxiheterociclos trisustituidos y análogos
JP2019517564A (ja) 2016-06-09 2019-06-24 ブリンクバイオ インコーポレイテッド シラノール系治療的ペイロード
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Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5359100A (en) * 1987-10-15 1994-10-25 Chiron Corporation Bifunctional blocked phosphoramidites useful in making nucleic acid mutimers
DK8892D0 (da) * 1992-01-23 1992-01-23 Symbicom Ab Humant proteingen
JPH08302016A (ja) 1995-04-27 1996-11-19 Sumitomo Durez Co Ltd シロキサン変性ポリイミド樹脂組成物
WO1998054255A1 (fr) 1997-05-30 1998-12-03 Shiseido, Co., Ltd. Copolymere contenant des groupes silyles reactifs, compositions contenant ce copolymere et methode de traitement afferente
CN1157602C (zh) 1997-09-05 2004-07-14 松下电器产业株式会社 荧光偏振法检测样品的方法及其中使用的试剂
US6326478B1 (en) * 1998-07-08 2001-12-04 Isis Pharmaceuticals, Inc. Process for the synthesis of oligomeric compounds
GB0111459D0 (en) 2001-05-10 2001-07-04 Isis Innovation Universal fluorescent sensors
US20100081792A1 (en) 2001-06-28 2010-04-01 Smithkline Beecham Corporation Ligand
AU2003290561A1 (en) 2003-02-10 2004-09-06 Dana Ault-Riche Self-assembling arrays and uses thereof
US7511139B2 (en) * 2004-06-04 2009-03-31 Bristol-Myers Squibb Company Process for the preparation of entecavir and novel intermediates thereof via carbon-silicon oxidation
BRPI0708942A2 (pt) * 2006-03-21 2011-06-14 Joyant Pharmaceuticals Inc composto promotor de apoptose, uso e mÉtodo de produÇço do mesmo e composiÇço farmacÊutica
US8062215B2 (en) 2007-04-13 2011-11-22 Ethicon Endo-Surgery, Inc. Fluorescent nanoparticle scope
PE20090242A1 (es) 2007-04-27 2009-04-04 Isdin Sa Compuestos de benzotriazolilfenol sililados sustituidos
US20100159446A1 (en) * 2007-07-27 2010-06-24 Haff Lawrence A Detection Assays and Use Thereof
AU2008284304A1 (en) * 2007-08-09 2009-02-12 Merck & Co., Inc. Silicon derivatives as histone deacetylase inhibitors
ES2396366T3 (es) * 2007-12-10 2013-02-21 Concert Pharmaceuticals Inc. Inhibidores heterocíclicos de quinasas
JP2011516547A (ja) * 2008-04-09 2011-05-26 コーネル ユニバーシティー コフェロンならびにその作製および使用方法
WO2011043817A1 (fr) 2009-10-07 2011-04-14 Cornell University Coférons et procédés de fabrication et d'utilisation de ceux-ci
EP2694707B1 (fr) 2011-04-07 2018-08-15 Cornell University Monomères aptes à dimériser dans une solution aqueuse et leurs procédés d'utilisation
EP2693883B1 (fr) * 2011-04-07 2018-12-26 Cornell University Monomères silyles aptes à former un multimère dans une solution aqueuse et leurs procédés d'utilisation
US20140161729A1 (en) 2011-04-07 2014-06-12 Cornell University Cofluorons and methods of making and using them
WO2015081280A1 (fr) * 2013-11-26 2015-06-04 Coferon, Inc. Ligands de bromodomaine pouvant se dimériser dans une solution aqueuse

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

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